tbuckley/cabot-search huggingface dataset:
Fecal microbiota transplantation from young mice rejuvenates aged hematopoietic stem cells by suppressing inflammation
Authors: Xiangjun Zeng, Xiaoqing Li, Xia Li, Cong Wei, Ce Shi, Kejia Hu, Delin Kong, Qian Luo, Yulin Xu, Wei Shan, Meng Zhang, Jimin Shi, Jingjing Feng, Yingli Han, He Huang, Pengxu Qian
Journal: Blood (2023)

Hematopoietic stem cell (HSC) aging is accompanied by hematopoietic reconstitution dysfunction, including loss of regenerative and engraftment ability, myeloid differentiation bias, and elevated risks of hematopoietic malignancies. Gut microbiota, a key regulator of host health and immunity, has recently been reported to affect hematopoiesis. However, there is currently limited empirical evidence explaining the direct impact of gut microbiome on aging hematopoiesis. In this study, we performed fecal microbiota transplantation (FMT) from young mice to aged mice and observed a significant increment in lymphoid differentiation and decrease in myeloid differentiation in aged recipient mice. Furthermore, FMT from young mice rejuvenated aged HSCs with enhanced short-term and long-term hematopoietic repopulation capacity. Mechanistically, single-cell RNA sequencing deciphered that FMT from young mice mitigated inflammatory signals, upregulated the FoxO signaling pathway, and promoted lymphoid differentiation of HSCs during aging. Finally, integrated microbiome and metabolome analyses uncovered that FMT reshaped gut microbiota composition and metabolite landscape, and Lachnospiraceae and tryptophan-associated metabolites promoted the recovery of hematopoiesis and rejuvenated aged HSCs. Together, our study highlights the paramount importance of the gut microbiota in HSC aging and provides insights into therapeutic strategies for aging-related hematologic disorders.
Targeting RNA Exonuclease XRN1 Potentiates Efficacy of Cancer Immunotherapy
Authors: Xue-Bin Ran, Ling-Wen Ding, Qiao-Yang Sun, Henry Yang, Jonathan W. Said, Lao Zhentang, Vikas Madan, Pushkar Dakle, Jin-Fen Xiao, Xinyi Loh, Ying Li, Liang Xu, Xiao-Qiang Xiang, Ling-Zhi Wang, Boon Cher Goh, De-Chen Lin, Wee Joo Chng, Soo-Yong Tan, Sudhakar Jha, H. Phillip Koeffler
Journal: Cancer Research (2023)

Abstract Despite the remarkable clinical responses achieved with immune checkpoint blockade therapy, the response rate is relatively low and only a subset of patients can benefit from the treatment. Aberrant RNA accumulation can mediate IFN signaling and stimulate an immune response, suggesting that targeting RNA decay machinery might sensitize tumor cells to immunotherapy. With this in mind, we identified an RNA exoribonuclease, XRN1, as a potential therapeutic target to suppress RNA decay and stimulate antitumor immunity. Silencing of XRN1 suppressed tumor growth in syngeneic immunocompetent mice and potentiated immunotherapy efficacy, while silencing of XRN1 alone did not affect tumor growth in immunodeficient mice. Mechanistically, XRN1 depletion activated IFN signaling and the viral defense pathway; both pathways play determinant roles in regulating immune evasion. Aberrant RNA-sensing signaling proteins (RIG-I/MAVS) mediated the expression of IFN genes, as depletion of each of them blunted the elevation of antiviral/IFN signaling in XRN1-silenced cells. Analysis of pan-cancer CRISPR-screening data indicated that IFN signaling triggered by XRN1 silencing is a common phenomenon, suggesting that the effect of XRN1 silencing may be extended to multiple types of cancers. Overall, XRN1 depletion triggers aberrant RNA-mediated IFN signaling, highlighting the importance of the aberrant RNA-sensing pathway in regulating immune responses. These findings provide the molecular rationale for developing XRN1 inhibitors and exploring their potential clinical application in combination with cancer immunotherapy. Significance: Targeting XRN1 activates an intracellular innate immune response mediated by RNA-sensing signaling and potentiates cancer immunotherapy efficacy, suggesting inhibition of RNA decay machinery as a novel strategy for cancer treatment.
Assessing the use of biologic therapy for psoriasis in Latin America
Authors: Francisco G Bravo
Journal: British Journal of Dermatology (2023)

Journal Article Assessing the use of biologic therapy for psoriasis in Latin America Get access Francisco G Bravo Francisco G Bravo Universidad Peruana Cayetano Heredia, Angamos 896, Miraflores, Lima 18, Peru Correspondence: Francisco G. Bravo. Email: fbravopuccio@gmail.com; francisco.bravo@upch.pe https://orcid.org/0000-0001-6584-0391 Search for other works by this author on: Oxford Academic Google Scholar British Journal of Dermatology, Volume 188, Issue 4, April 2023, Page 454, https://doi.org/10.1093/bjd/ljad003 Published: 13 January 2023 Article history Received: 28 December 2022 Published: 13 January 2023 Corrected and typeset: 06 February 2023
Reply to Wang and Zhou
Authors: Katharina Jandl, Leigh M. Marsh, Ayse Ceren Mutgan, Slaven Crnkovic, Francesco Valzano, Diana Zabini, Julia Hoffmann, Vasile Foris, Elisabeth Gschwandtner, Walter Klepetko, Helmut Prosch, Holger Flick, Luka Brcic, Izidor Kern, Akos Heinemann, Horst Olschewski, Gabor Kovacs, Grazyna Kwapiszewska
Journal: American Journal of Respiratory and Critical Care Medicine (2023)

"Reply to: Targeting Pulmonary Hypertension Caused by Pulmonary Fibrosis: A Promising NKT Cell-based Therapy." American Journal of Respiratory and Critical Care Medicine, 0(ja), pp. –
ASPM Activates Hedgehog and Wnt Signaling to Promote Small Cell Lung Cancer Stemness and Progression
Authors: Li-Hsin Cheng, Chung-Chi Hsu, Hung-Wen Tsai, Wen-Ying Liao, Pei-Ming Yang, Tai-Yan Liao, Hsiao-Yen Hsieh, Tze-Sian Chan, Kelvin K. Tsai
Journal: Cancer Research (2023)

Small cell lung cancer (SCLC) is among the most aggressive and lethal human malignancies. Most patients with SCLC who initially respond to chemotherapy develop disease relapse. Therefore, there is a pressing need to identify novel driver mechanisms of SCLC progression to unlock treatment strategies to improve patient prognosis. SCLC cells comprise subsets of cells possessing progenitor or stem cell properties, while the underlying regulatory pathways remain elusive. Here, we identified the isoform 1 of the neurogenesis-associated protein ASPM (ASPM-I1) as a prominently upregulated stemness-associated gene during the self-renewal of SCLC cells. The expression of ASPM-I1 was found to be upregulated in SCLC cells and tissues, correlated with poor patient prognosis, and indispensable for SCLC stemness and tumorigenesis. A reporter array screening identified multiple developmental signaling pathways, including Hedgehog (Hh) and Wnt pathways, whose activity in SCLC cells depended upon ASPM-I1 expression. Mechanistically, ASPM-I1 stabilized the Hh transcriptional factor GLI1 at the protein level through a unique exon-18-encoded region by competing with the E3 ligases β-TrCP and CUL3. In parallel, ASPM-I1 sustains the transcription of the Hh pathway transmembrane regulator SMO through the Wnt-DVL3-β-catenin signaling axis. Functional studies verified that the ASPM-I1-regulated Hh and Wnt activities significantly contributed to SCLC aggressiveness in vivo. Consistently, the expression of ASPM-I1 positively correlated with GLI1 and stemness markers in SCLC tissues. This study illuminates an ASPM-I1-mediated regulatory module that drives tumor stemness and progression in SCLC, providing an exploitable diagnostic and therapeutic target.ASPM promotes SCLC stemness and aggressiveness by stabilizing the expression of GLI1, DVL3, and SMO, representing a novel regulatory hub of Hh and Wnt signaling and targetable vulnerability.
Malaria parasite prevalence in Sub-Saharan African migrants screened in Sweden: a cross-sectional study
Authors: Andreas Wångdahl, Rebecca Tafesse Bogale, Isabelle Eliasson, Ioanna Broumou, Fariba Faroogh, Filip Lind, Ganna Vashchuk, Adina Hildell, Suzanne Franson, Emil Hallberg, Isabelle Grip, Irene Nordling, Angelica Gervin, Shelan Kaitoly, Berhane Tekleab, Katja Wyss, Ana Requena-Méndez, Olof Hertting, Anna Färnert
Journal: The Lancet Regional Health - Europe (2023)

Asymptomatic infections with malaria parasites are common in populations in endemic areas. These infections may persist in migrants after arrival in a non-endemic area. Screening to find and clear these infections is generally not implemented in non-endemic countries, despite a potential negative health impact. We performed a study to evaluate the Plasmodium parasite prevalence in migrants living in Sweden.Adults and children born in Sub-Saharan Africa (SSA) were invited in the study between April 2019 and June 2022 at 10 different sites, mainly as part of the national Migrant Health Assessment Program in Stockholm and Västerås, Sweden. Rapid diagnostic tests (RDT) and real-time PCR were used to detect malaria parasites. Prevalence and test sensitivity were calculated with 95% confidence intervals (CI). Univariate and multivariable logistic regression were used to evaluate associations with PCR positivity.In total, 789 individuals were screened for Plasmodium spp. of which 71 (9.0%) were positive by PCR and 18 (2.3%) also by RDT. When performed during the national screening program, 10.4% was PCR positive. A high prevalence was detected in migrants with Uganda as the country of last residence, 53/187 (28.3%), and in this group the prevalence was highest in children, 29/81 (35.8%). Among the PCR positive, 47/71 (66.2%) belonged to families with at least one other member testing positive (odds ratio [OR] 43.4 (95% CI 19.0-98.9), and the time lived in Sweden ranged between 6 and 386 days.A high malaria parasite prevalence was found in migrants from SSA, particularly in children offered screening in Stockholm, Sweden during the study period. Awareness of asymptomatic malaria infection is needed and screening for malaria in migrants arriving from high endemic countries should be considered.The Swedish Research Council, Stockholm County Council and Centre for Clinical Research, Västmanland, Sweden.
The Role of 68Ga-FAPI PET/CT in Detection of Metastatic Lobular Breast Cancer
Authors: Yael Eshet, Noam Tau, Sara Apter, Noam Nissan, Keren Levanon, Rinat Bernstein-Molho, Ofer Globus, Amit Itay, Tal Shapira, Cecilie Oedegaard, Malka Gorfine, Michal Eifer, Tima Davidson, Einav Gal-Yam, Liran Domachevsky
Journal: Clinical Nuclear Medicine (2023)

Purpose Invasive lobular breast cancer (ILC) may be hard to detect using conventional imaging modalities and usually shows less avidity to 18 F-FDG PET/CT. 68 Ga–fibroblast activation protein inhibitor (FAPI) PET/CT has shown promising results in detecting non– 18 F-FDG–avid cancers. We aimed to assess the feasibility of detecting metastatic disease in patients with non– 18 F-FDG–avid ILC. Methods This prospective study included patients with metastatic ILC, infiltrative to soft tissues, which was not 18 F-FDG avid. The patients underwent 68 Ga-FAPI PET/CT for evaluation, which was correlated with the fully diagnostic CT performed at the same time. Results Seven women (aged 57 ± 10 years) were included. Among the 30 organs and structures found to be involved by tumor, the number of findings observed by FAPI PET/CT was significantly higher than that observed by CT alone ( P = 0.022), especially in infiltrative soft tissue and serosal locations. Conclusions This small pilot trial suggests a role for 68 Ga-FAPI PET/CT in ILC, which needs to be confirmed by subsequent trials.
Estimated Testing, Tracing, and Vaccination Targets for Containment of the US Mpox Outbreak
Authors: Melanie H. Chitwood, Jiye Kwon, Alexandra Savinkina, Jo Walker, Alyssa Bilinski, Gregg Gonsalves
Journal: JAMA Network Open (2023)

This decision analytic model estimates the levels of community testing, contract tracing, and vaccination required to reduce the effective reproduction number of the mpox virus among the high-risk group of men who have sex with men.
Incidence, Severity, and Presentation of Type 2 Diabetes in Youth During the First and Second Year of the COVID-19 Pandemic
Authors: Sabitha Sasidharan Pillai, Phinnara Has, Jose Bernardo Quintos, Monica Serrano Gonzalez, Vania L. Kasper, Lisa Swartz Topor, Meghan E. Fredette
Journal: Diabetes Care (2023)

OBJECTIVE To describe the evolving impact of the coronavirus disease 2019 pandemic on the incidence and presentation of new-onset pediatric type 2 diabetes. RESEARCH DESIGN AND METHODS Retrospective medical record review of youth with new-onset type 2 diabetes comparing the prepandemic period (1 January 2017–29 February 2020) with the first (1 March 2020–31 December 2020) and second pandemic year (1 January 2021–31 December 2021). RESULTS The annualized incidence of type 2 diabetes increased nearly threefold during the pandemic versus prior, with a 61% increase in the 2nd versus 1st year. BMI increased during the pandemic versus prior (129% of 95th percentile vs. 141%, P = 0.02). In the 1st year, patients were younger (12.9 years vs. 14.8, P &amp;lt; 0.001), with higher incidence of diabetic ketoacidosis and/or hyperglycemic hyperosmolar syndrome (20% vs. 3.5%, P = 0.02) versus prior. CONCLUSIONS Providers should be aware of the escalating incidence of youth-onset type 2 diabetes to avoid delays in diagnosis and inform educational programs to combat the continued impact of the pandemic on health outcomes.
Targeted GATA3 knockdown in activated T cells via pulmonary siRNA delivery as novel therapy for allergic asthma
Authors: Rima Kandil, Domizia Baldassi, Sebastian Böhlen, Joschka T. Müller, David C. Jürgens, Tonia Bargmann, Susann Dehmel, Yuran Xie, Aditi Mehta, Katherina Sewald, Olivia M. Merkel
Journal: Journal of Controlled Release (2023)
Loss of CRY2 promotes regenerative myogenesis by enhancing PAX7 expression and satellite cell proliferation
Authors: Yingxue Hao, Ting Xue, Song‐Bai Liu, Sha Geng, Xinghong Shi, Panting Qian, Wei He, Jiqing Zheng, Yanfang Li, Jing Lou, Tianze Shi, Ge Wang, Xiaoxiao Wang, Yanli Wang, Yangxin Li, Yao‐Hua Song
Journal: MedComm (2023)

Abstract The regenerative capacity of skeletal muscle is dependent on satellite cells. The circadian clock regulates the maintenance and function of satellite cells. Cryptochrome 2 (CRY2) is a critical component of the circadian clock, and its role in skeletal muscle regeneration remains controversial. Using the skeletal muscle lineage and satellite cell‐specific CRY2 knockout mice (CRY2 scko ), we show that the deletion of CRY2 enhances muscle regeneration. Single myofiber analysis revealed that deletion of CRY2 stimulates the proliferation of myoblasts. The differentiation potential of myoblasts was enhanced by the loss of CRY2 evidenced by increased expression of myosin heavy chain (MyHC) and myotube formation in CRY2 −/− cells versus CRY2 +/+ cells. Immunostaining revealed that the number of mononucleated paired box protein 7 (PAX7 + ) cells associated with myotubes formed by CRY2 −/− cells was increased compared with CRY2 +/+ cells, suggesting that more reserve cells were produced in the absence of CRY2. Loss of CRY2 leads to the activation of the ERK1/2 signaling pathway and ETS1, which binds to the promoter of PAX7 to induce its transcription. CRY2 deficient myoblasts survived better in ischemic muscle. Therefore, CRY2 is essential in regulating skeletal muscle repair.
Validation of diagnostic criteria for atopic dermatitis and proposal of novel diagnostic criteria for adult and elderly Chinese populations: a multicentre, prospective, clinical setting-based study
Authors: Wanbo Yue, Daian Cheng, Zhe Sun, Yihang Shen, Shangshang Wang, Xiumei Liu, Xiaoping Pei, Sisi Deng, Hongju Pan, Zhigang Liao, Wei Li, Xu Yao, Yunsheng Liang, Zhiqiang Song, Zhirong Yao, Hui Zhang, Yifeng Guo
Journal: British Journal of Dermatology (2022)

Abstract Background A previous validation study showed a very low sensitivity and higher specificity associated with Hanifin and Rajka criteria (H&amp;R) and the UK Working Party criteria (UKWP) in diagnosing AD vs. the Chinese criteria of atopic dermatitis (AD) for children (CCAD). However, their diagnostic efficacy in adult and elderly Chinese populations remains unknown. Objectives To validate the diagnostic efficacy of three sets of AD criteria in adult and elderly Chinese populations in a hospital setting. Methods A total of 1034 patients (aged 19–95 years) from five university hospital dermatological clinics were recruited. Medical history, dermatological examination, AD diagnosis and evaluation of AD severity were done by dermatologists. Each patient was investigated by two dermatologist panels, one to establish a clinical diagnosis, and the other to identify and record the major or minor signs of H&amp;R criteria, UKWP criteria and CCAD. Taking clinical diagnosis as the reference, the diagnostic efficacy of three sets of diagnostic criteria was evaluated. The χ2 test or rank sum test were used for between-groups comparisons. Results CCAD had a higher sensitivity (84.0%), especially among mild and moderate cases of AD (72.7% and 90.3%, respectively), than the H&amp;R (58.0%; P &amp;lt; 0.001) and UKWP criteria (56.0%; P &amp;lt; 0.001) in diagnosing AD. The specificity of CCAD (92.7%) was slightly lower than the H&amp;R (97.3%; P &amp;lt; 0.001) or UKWP criteria (97.4%; P &amp;lt; 0.001). The CCAD had the highest Youden index (0.77), accuracy rate (0.90) and Kappa value (0.76) of the three sets of diagnostic criteria. Conclusions Consistent with results in a population of Chinese children, although the H&amp;R and UKWP criteria had a high specificity for diagnosing AD, their low sensitivity limited their use in adult and elderly Chinese patients. Based on the high sensitivity and favourable diagnostic efficacy, the CCAD is proposed for AD diagnosis in adult and elderly Chinese populations, especially for cases of mild and moderate AD.
SGLT2 inhibitors mitigate kidney tubular metabolic and mTORC1 perturbations in youth-onset type 2 diabetes
Authors: Jennifer A. Schaub, Fadhl M. AlAkwaa, Phillip J. McCown, Abhijit S. Naik, Viji Nair, Sean Eddy, Rajasree Menon, Edgar A. Otto, Dawit Demeke, John Hartman, Damian Fermin, Christopher L. O’Connor, Lalita Subramanian, Markus Bitzer, Roger Harned, Patricia Ladd, Laura Pyle, Subramaniam Pennathur, Ken Inoki, Jeffrey B. Hodgin, Frank C. Brosius, Robert G. Nelson, Matthias Kretzler, Petter Bjornstad
Journal: Journal of Clinical Investigation (2023)

The molecular mechanisms of sodium-glucose cotransporter-2 (SGLT2) inhibitors (SGLT2i) remain incompletely understood. Single-cell RNA sequencing and morphometric data were collected from research kidney biopsies donated by young persons with type 2 diabetes (T2D), aged 12 to 21 years, and healthy controls (HCs). Participants with T2D were obese and had higher estimated glomerular filtration rates and mesangial and glomerular volumes than HCs. Ten T2D participants had been prescribed SGLT2i (T2Di[+]) and 6 not (T2Di[-]). Transcriptional profiles showed SGLT2 expression exclusively in the proximal tubular (PT) cluster with highest expression in T2Di(-) patients. However, transcriptional alterations with SGLT2i treatment were seen across nephron segments, particularly in the distal nephron. SGLT2i treatment was associated with suppression of transcripts in the glycolysis, gluconeogenesis, and tricarboxylic acid cycle pathways in PT, but had the opposite effect in thick ascending limb. Transcripts in the energy-sensitive mTORC1-signaling pathway returned toward HC levels in all tubular segments in T2Di(+), consistent with a diabetes mouse model treated with SGLT2i. Decreased levels of phosphorylated S6 protein in proximal and distal tubules in T2Di(+) patients confirmed changes in mTORC1 pathway activity. We propose that SGLT2i treatment benefits the kidneys by mitigating diabetes-induced metabolic perturbations via suppression of mTORC1 signaling in kidney tubules.
Advancing rapid cycle research in cancer care delivery: a National Cancer Institute workshop report
Authors: Wynne E Norton, Amy E Kennedy, Brian S Mittman, Gareth Parry, Shobha Srinivasan, Emily Tonorezos, Robin C Vanderpool, Paul B Jacobsen
Journal: JNCI Journal of the National Cancer Institute (2023)

Abstract Generating actionable research findings quickly and efficiently is critical for improving the delivery of cancer-related care and outcomes. To address this issue, the National Cancer Institute convened subject matter experts, researchers, clinicians, and patients for a 2-day virtual meeting in February 2022. The purpose of this meeting was to identify how rapid cycle interventional research methods can be used to generate findings useful in improving routine clinical practice. The meeting yielded an initial conceptualization of rapid cycle interventional research as being comprised of 6 key elements: use of iterative study designs; reliance on proximal primary outcomes; early and continued engagement with community and clinical partners; use of existing data sources to measure primary outcomes; facilitative features of the study setting and context; and consideration of appropriate rigor relative to intended use of findings. The meeting also identified the types of study designs that can be leveraged to conduct rapid cycle interventional research and provided examples of these; considered this approach from the perspective of key partners; described the clinical and data infrastructure, research resources, and key collaborations needed to support this work; identified research topics best addressed using this approach; and considered needed methodological advances. The National Cancer Institute is committed to exploring opportunities to encourage further development and application of this research approach as a means for better promoting improvements in the delivery of cancer-related care.
Regulators of male and female sexual development are critical for the transmission of a malaria parasite
Authors: Andrew J.C. Russell, Theo Sanderson, Ellen Bushell, Arthur M. Talman, Burcu Anar, Gareth Girling, Mirjam Hunziker, Robyn S. Kent, Julie S. Martin, Tom Metcalf, Ruddy Montandon, Vikash Pandey, Mercedes Pardo, A. Brett Roberts, Claire Sayers, Frank Schwach, Jyoti S. Choudhary, Julian C. Rayner, Thierry Voet, Katarzyna K. Modrzynska, Andrew P. Waters, Mara K.N. Lawniczak, Oliver Billker
Journal: Cell Host & Microbe (2023)

Malaria transmission to mosquitoes requires a developmental switch in asexually dividing blood-stage parasites to sexual reproduction. In Plasmodium berghei, the transcription factor AP2-G is required and sufficient for this switch, but how a particular sex is determined in a haploid parasite remains unknown. Using a global screen of barcoded mutants, we here identify genes essential for the formation of either male or female sexual forms and validate their importance for transmission. High-resolution single-cell transcriptomics of ten mutant parasites portrays the developmental bifurcation and reveals a regulatory cascade of putative gene functions in the determination and subsequent differentiation of each sex. A male-determining gene with a LOTUS/OST-HTH domain as well as the protein interactors of a female-determining zinc-finger protein indicate that germ-granule-like ribonucleoprotein complexes complement transcriptional processes in the regulation of both male and female development of a malaria parasite.
Economic Burden of the 2020 COVID-19 Hospitalizations in Spain
Authors: Blanca Álvarez-del Río, Laura Sánchez-de Prada, Alejandro Álvaro-Meca, Marta Martín-Fernández, F. Javier Álvarez, Eduardo Tamayo, Eduardo Gutiérrez-Abejón
Journal: JAMA Network Open (2023)

This economic evaluation reports the total and per patient costs of inpatient care for COVID-19 in Spain in 2020.